Use of sebacic acid and derivatives thereof in enteral and parenteral nutrition and pharmaceutical compositions containing said compounds

ABSTRACT

Sebacic acid and the pharmacologically acceptable derivatives thereof, such as the novel compounds sodium sebacate and potassium sebacate, the sebacic acid triglyceride and the sodium and potassium salts of the triglyceride are useful for manufacturing pharmaceutical compositions suitable for the enteral and parenteral nutrition.

The present invention relates to the use of sebacic acid andpharmacologically acceptable sebacic acid derivatives in enteral andparenteral nutrition.

According to the present invention, by "pharmacologically acceptablesebacic acid derivatives" the following compounds are meant: thepharmacologically acceptable salts, particularly the alkaline metalsalts, preferably the sodium and potassium salts, the sebacic acidtriglyceride and the pharmacologically acceptable salts thereof,preferably the sodium and potassium salts. The sodium and potassiumsalts of the sebacic acid triglycerides are novel compounds.

In clinical practice, whereas lipid emulsions of triglycerides of longchain monocarboxylic fatty acids have been in general use for totalparenteral nutrition for a number of years, only recently the use ofsome medium chain triglycerides has met with satisfactory results.However, these emulsions suffer from serious drawbacks. Indeed, in somefrequently occurring pathological conditions, such as sepsis,conflicting experimental evidences do exist as to the effectively viableutilization of long chain triglycerides. Supposedly, this impairedutilization would be caused by a relative deficiency of carnitine which,in turn, would bring about an impaired mitochondrial oxidation of longchain fatty acids. Further experimental evidences suggest that highdoses of medium chain triglycerides administered to experiment animalswherein ketoacidosis had been induced can bring about toxic effectsencompassing narcosis. It is, therefore, felt the need of relying onsubstrates other than those used to-date.

It has now been found that sebacic acid and the afore-saidpharmacologically acceptable derivatives thereof are an excellentsubstrate for manufacturing compositions suitable for enteral andparenteral nutrition, which do not present the drawbacks of the knownsubstrates.

The present invention provides, therefore, pharmaceutical compositionssuited for enteral and parenteral administration characterized in thatthey comprise, as active principle, sebacic acid or a derivativethereof. Particularly, the sebacic acid derivative is selected from thepharmacologically acceptable sebacic acid salts, the sebacic acidtriglyceride and the pharmacologically acceptable salts of the sebacicacid triglyceride. Preferably, the pharmacologically acceptable salt ofsebacic acid or sebacic acid triglyceride is selected from the sodiumand the potassium salts.

The pharmaceutical compositions, when they are formulated as aqueoussolutions, comprise from 0.2 to 0.6 moles/liter of a pharmacologicallyacceptable salt of sebacic acid or from 0.2 to 1 moles/liter of sebacicacid triglyceride or a pharmacologically acceptable salt of sebacic acidtriglyceride. Preferably, they comprise 0.5 moles/liter of salt,triglyceride or triglyceride salt of sebacic acid.

The orally administrable compositions in unit dosage form, e.g.capsules, comprise from 0.5 to 1.5 grams of salt, trigliceride ortriglyceride salt of sebacic acid.

Sodium and potassium sebacate are prepared by neutralization of sebacicacid (C10) with NaOH or KOH (molar ratio OH-:C10 2:1).

In order to prepare the sodium and potassium salts of sebacic acidtriglyceride, sebacic acid is added to thionyl chloride (b.p. 79° C.) indioxane freshly distilled over lithium and aluminum hydroxide (molarratio C10:thionyl chloride 1:2), keeping the resulting mixture at thereflux temperature for 5-6 hours in the presence of cesium chloride ascatalyst. By removing dioxane under vacuum the acid chloride of sebacicacid is obtained.

The triglyceride is dissolved in distilled water in the presence ofsmall amounts of magnesium as catalyst and NaOH to maintain the solutionpH at about 8 and to form, by reacting with HCl that frees from theesterification reaction, NaCl and H₂ O when C10 acid chloride is addedto the reaction mixture.

To this aqueous solution, an excess amount of C10 acid chloridedissolved in dioxane (5-8 times the glycerol amount, lest thepolymerization of the compound thus formed may occur) is slowly added ina nitrogen atmosphere, while taking care to maintain a basic pH byaddition of small NaOH portions. The reaction reaches completion inabout 30 minutes, if small amounts of reagents are used. Doubledistilled water is then added in order to obtain a clear solution andthe excess of free acids is removed via three extractions with diethylether. Traces of ether dissolved in the solution are removed by bubblingnitrogen therein. Finally, the solution is dialyzed against doubledistilled water for 24 hours, in order to remove the alkaline metalchloride.

Neither sebacic acid nor its derivatives according to the presentinvention are toxic.

Acute toxicity tests following oral and intraperitoneal administrationof disodium sebacate to Wistar rats (128 rats, 64 male and 64 female)and New Zealand rabbits (128 rabbits, 64 male and 64 female) did notallow LD₅₀ to be assessed. Similarly, subacute and chronic toxicitieswere studied in 40 rats (20 male and 20 female) and 40 rabbits (20 maleand 20 female) that had been administered sebacic acid formulated intopellets. No significant difference in biological parameters (haematicvalues, growing curves, the taking of histologic samples from variousorgans) was detected in the treated animals compared with the controlanimals. Moreover, fetal toxicity tests, teratogenesis tests andneonatal toxicity tests performed on rats and rabbits did not allow anytoxicity effect to be detected. In particular, no teratogenic effect wasever noticed whilst fetal development was absolutely normal.

Sodium and potassium sebacates, too, do not exhibit particular acute orchronic toxic effects in rats and rabbits. Since the same death rate isfound in animals administered saline only containing a high sodiumamount, it is apparent that toxicity is to be attributed to sodium.

Finally, alkaline metal sebacates are not toxic towards fetuses andnewly-born animals even when the mothers are administered high doses ofsebacate during pregnancy.

In man, too, no toxic effects were found even following long-termtreatment.

On the other hand, sebacic acid and its derivatives are easilymetabolized since they are beta-oxidized and CoA-activated not only inmitochondria, as it occurs for the fatty acids used to-date, but also inperoxisomes down to the level of C6 that, freed in cytoplasm, can enterthe mitochondria via a carnitine acyl transferase-independent pathway.

This particular metabolic pathway makes these compounds highly suited insepsis conditions, since their metabolism is influenced to a lesserdegree by a carnitine decrease.

Moreover, in comparison with the fatty substrates in use to-date, thecompounds of the present invention exhibit a high molar ratio ATP/CO₂,i.e. a higher energy output with an attendant lower CO₂ production. Thisis particularly advantageous in patients presenting alterations inrespiratory parameters.

In those cases wherein the administration of a reduced sodium amount isof major importance, the triglyceride salt will be the compound ofchoice since it contains half the sodium amount of the correspondingsebacate.

The effectiveness and advantages of the substrates for enteral andparenteral nutrition according to the present invention were assessed byseveral clinical trials. One of these is hereinbelow briefly outlined.

Two groups of healthy male volunteers were admitted to the trial. Thefirst group, composed of 6 subjects, received 1000 mg sebacate as abolus; 6 other subjects (second group) received 10 g sebacate dissolvedin 500 ml of double distilled water at an infusion rate of 3.33 g/h over3 hours. The serum sebacate data for each subject were analysed bycomputer, using biexponential fit corresponding to a 2-compartment openmodel. The distribution half-life (t_(1/2)) was 0.34±0.06 h and theelimination phase was rather rapid (Ke=2.10±0.38 h⁻¹); the volume of thecentral compartment was 2.79±0.54 l and the volume of tissue compartment3.72±0.14 l. These data showed a good tissue fixation of sebacate. Theplasma clearance was evaluated to be 5.96±2.19 l/h and the renalclearance 19.22±10.69 l/h, indicating that a tubular secretion ofsebacic acid had taken place. The serum concentration of sebacate raisedto its peak value at the end of the infusion (180 min) and correspondedto 480.50±43.02 μg/ml.

Respiratory and metabolic parameters were evaluated by indirectcalorimetry from the beginning of the infusion for 210 minutes. The O₂consumption (VO₂ ml/min/m²) remained essentially unchanged throughoutthe experiment (from 154.3±28.3 at time 0 to 155.3±39.5 at time 180min). The CO₂ production (VCO₂ ml/min/m²) decreased below basal values(147.7±27.3) up to 123.7±25.0 at the end of the infusion. Thusrespiratory quotient (RQ) decreased significantly (from 0.96±0.04 to0.81±0.06) and the percent of calories derived from lipids increasedduring and after the infusion (from -0.13±13.3 to 52.1±26.2). Metabolicrate (MR Kcal/h/m²) remained constant during the entire study period.

In this trial, the urinary excretion of sebacic acid and its products ofbeta-oxidition (suberic (C8) and adipic ((C6) acids) was found to be low(totaling less than 16% of the administered dose). The energy productionwas high (6.64 Kcal/g), sebacic acid being completely oxidized in thebody to CO₂ and H₂ O.

I claim:
 1. A method of providing nutrition to a patient in need thereofcomprising administering an effective amount of sebacic acid or apharmacologically acceptable derivative thereof.
 2. The method accordingto claim 1, wherein said pharmacologically acceptable derivative ofsebacic acid is selected from the group comprising sebacic acid, sebacicacid triglyceride and pharmaceutically acceptable salts of sebacic acidtriglyceride.
 3. The method according to claim 2, wherein thepharmaceutically acceptable salt of sebacic acid or sebacic acidtriglyceride is selected from the group consisting of sodium salt andpotassium salt.
 4. The method according to claim 1, wherein said sebacicacid or pharmacologically acceptable derivative thereof is administeredas an aqueous solution comprising from 0.2 to 1 mol/liter of sebacicacid triglyceride or a pharmaceutically acceptable salt of sebacic acidtriglyceride.
 5. The method according to claim 4, wherein said sebacicacid or pharmacologically acceptable derivative thereof is administeredas an aqueous solution comprising about 0.5 moles/liter of sebacic acidtriglyceride or a pharmaceutically acceptable salt of sebacic acidtriglyceride.
 6. The method according to claim 1, wherein said sebacicacid or pharmacologically acceptable derivative thereof is suitable fororal administration and wherein said effective amount comprises from 0.5to 1.5 grams of sebacic acid triglyceride or a pharmaceuticallyacceptable salt of sebacic acid triglyceride.
 7. The method according toclaim 6, wherein said sebacic acid or pharmacologically acceptablederivative thereof is formulated as a capsule.
 8. The method accordingto claim 1, wherein the pharmacologically acceptable derivative is analkaline metal salt of sebacic acid triglyceride.